Regiocontrolled synthesis of highly-functionalized fused imidazoles: A novel synthesis of second generation LFA-1 inhibitors

Article abstract of DOI:10.1016/S0040-4039(03)01535-1

A new and reliable route to a new class of LFA-1 inhibitors such as (2) has been developed. A key aspect of this route is the transformation of amino amide 5 into iodide 3 in four steps. Iodide 3 is a key advanced intermediate used in the synthesis of all

Full text of DOI:10.1016/S0040-4039(03)01535-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6509–6511
Regiocontrolled synthesis of highly-functionalized fused
imidazoles: a novel synthesis of second generation
LFA-1 inhibitors
Rogelio P. Frutos* and Michael Johnson
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd./PO Box 368,
Ridgefield, CT 06877-0368, USA
Received 16 April 2003; revised 15 June 2003; accepted 15 June 2003
Abstract—A new and reliable route to a new class of LFA-1 inhibitors such as (2) has been developed. A key aspect of this route
is the transformation of amino amide 5 into iodide 3 in four steps. Iodide 3 is a key advanced intermediate used in the synthesis
of all second-generation 1H-imidazo[1,2-a]imidazol-2-one LFA-1 inhibitors.
© 2003 Elsevier Ltd. All rights reserved.
Lymphocytes are cells of the immune system that must
balance their dual role of surveillance and responsive-
ness as they patrol the body in search of foreign
antigens. In their surveillance role, they must circulate
freely in the blood and lymph in a non-adherent (unac-
tivated) state. In the presence of a foreign antigen,
however, these cells must become activated quickly,
cross membrane walls, congregate at the site of infec-
tion and adhere to and destroy the invading cells
bearing the foreign antigen. The interactions between
cells that direct lymphocyte activation, migration and
localization are mediated by cell-surface molecules
known as adhesion receptors.1 LFA-1 (lymphocyte
function-related antigen) belongs to the integrin family
of receptors associated with the role of regulating adhe-
sion and migration of lymphocytes, and the counter
receptor to LFA-1 on target cells is recognized to be
ICAM-1 (intercellular cell adhesion molecule).
The selection 2 and related compounds for further
pre-clinical studies created the need to develop a safe,
robust, reliable and scalable process suitable for the
synthesis of large amounts of these compounds. The
development of such process presented us with a num-
ber of challenges, as certain aspects of the original
discovery route were not ideal for scale-up due to the
use of potentially dangerous azide reagents and the
extensive use of silica gel chromatography.4 In addition,
a key step of the discovery route involved the direct
iodination of 4 to afford 3, and this reaction was not
regioselective and resulted in the formation of a mixture
of regioisomers that had to be separated by
chromatography.4,19
We focused our attention on the highly functionalized
vinyl iodide 3 (Scheme 1), as this compound is a key
precursor to all second generation 1H-imidazo[1,2-
a]imidazol-2-one LFA-1 inhibitors such as 2. There-
fore, a safer, efficient and scalable route to iodide 3
would not only make it possible to synthesize large
Blocking the protein–protein interaction of cell adhe-
sion molecules such as LFA-1 to ICAM-1 has the
potential to benefit patients suffering from immune
disorders. Accordingly,
a program to find small
molecule inhibitors of LFA-1 was initiated by our
discovery team and resulted in the finding of series of
hydantoins inhibitors such as BIRT377 (1).2 Further
SAR studies led to a series of structurally related
1H-imidazo[1,2-a]imidazol-2-ones such as compound 2
with improved pharmacological properties (Fig. 1).3
Keywords: imidazoles; LFA-1 inhibitors; vinyl iodides.
* Corresponding author. Tel.: 203-798-4681; fax: 203-791-6130;
e-mail: rfrutos@rdg.boehringer-ingelheim.com
Figure 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01535-1

6510
R. P. Frutos, M. Johnson / Tetrahedron Letters 44 (2003) 6509–6511
Scheme 3. Reagents and conditions: (a) i. ethyl isocyanoac-
etate, CH2Cl2, rt, 2.5 h; ii. Ph3P, CCl4, Et3N, rt, 12 h (81%);
(b) Me3Al, Ph3PO, toluene, 25°C (91%).
Scheme 1. Retrosynthesis analysis of iodides 3 and 2.
amounts of compounds such as 2, but it would also
facilitate the synthesis of analogs and expedite SAR
studies. Key objectives of our new synthesis of 3
(Scheme 1) would be to eliminate the use of azide
reagents and to replace the non-selective iodination of
4. Accordingly, our proposed synthesis of 3 is shown in
Scheme 1. Iodide 3 would be synthesized from interme-
diate 5, which has the same oxidation state as 3.
Intermediate 5 would be prepared from intermediate
urea 6, and 6 would come from amino amide 7, for
two-step synthesis of 8 into a one-pot procedure with-
out isolation of 6, and accomplished the direct synthesis
of 5 from 8 without going through intermediate 9.
Accordingly, treatment of 7 with ethyl isocyanoacetate
followed by in situ dehydration and cyclization of the
intermediate urea (6) afforded 8 in 81% yield. Heating
8 in the presence of acids or bases failed to produce 5,
but intermediate 8 could be converted to 5 using a
modification of Weinreb’s procedure for the conversion
of esters to amides.8,9
which a well-established synthetic route from
D-alanine
already exists.5
Our first generation synthesis of intermediate 5 is
shown in Scheme 2. Treatment of 7 with commercially
available ethyl isocyanoacetate afforded urea 6 in excel-
lent yield as a crystalline compound. Dehydration of
urea 6 upon treatment with Ph3P·CCl4/Et3N6 gave
intermediate 8 in good yield, presumably through a
transient carbodiimide that cyclizes spontaneously.7
Subsequent hydrolysis of 8 with LiOH gave carboxylic
acid 9, which was converted to its acyl chloride with
oxalyl chloride and triethylamine and cyclized under
the reaction conditions to afford 5 in 57% yield.
With a reliable source of 5 now available, we turned
our attention to the transformation of 5 into iodide 3.
The direct synthesis of vinyl halides such as chlorides
and bromides from amides and ketones with reagents
such as POCl3 or POBr3 is well known,11 but the
10
synthesis of vinyl iodides from carbonyl compounds is
far less common, and we could not find a literature
precedent for the direct or indirect transformation of
amides into vinyl iodides. There exist a number of
methods for the indirect synthesis of vinyl iodides from
ketones through intermediates such as hydrazones,12
vinyl trimethyltin compounds,13 triflates14 and vinyl
phosphates,15 and we decided to pursue the use of a
vinyl phosphate intermediate due to the reported higher
stability of such compounds relative to similar
triflates.16
Further optimization led to a more streamlined synthe-
sis of 5 (Scheme 3). We were able to combine the
Phosphate 10 was easily prepared from 5 in good yield
using standard conditions (KN(TMS)2, (EtO)2POCl,
THF), and could be purified by filtration through a
short plug of silica gel and stored for several weeks
without noticeable decomposition (Scheme 4). Phos-
phate 10 was then converted to 3 in 75% yield upon
treatment with NaI/TMSCl according to a modification
of the procedure described by Wiemer and co-workers15
in their synthesis of vinyl iodides from ketone-derived
vinyl phosphates. Interestingly, the formation of 3 was
faster and more reproducible when 0.7 to 1 equiv. of
water were added to the reaction mixture. There is very
little known about the mechanism for this transforma-
tion, but it is very likely that at least in our case, the
presence of hydrogen iodide generated by the TMSCl/
NaI/water17 system is crucial for the reaction.18
Scheme 2. Reagents and conditions: (a) ethyl isocyanoacetate,
CH2Cl2, rt, 2.5 h; (b) Ph3P, CCl4, Et3N, rt, 12 h (81%); (c) 1
M LiOH, THF, rt, 1 h; (d) (COCl)2, Et3N, THF, −20°C (57%
for two steps).
With a reliable and convenient route to intermediate 3
at hand, the preparation of second generation 1H-imi-

R. P. Frutos, M. Johnson / Tetrahedron Letters 44 (2003) 6509–6511
6511
B.-J.; Rothlein, R. J. Immunol. 1999, 163, 5173; (b)
Last-Barney, K.; Davidson, W.; Cardozo, M.; Frye, L.
L.; Grygon, C. A.; Hopkins, J. L.; Jeanfavre, D. D.; Pav,
S.; Qian, C.; Stevenson, J. M.; Tong, L.; Zindell, R.;
Kelly, T. A. J. Am. Chem. Soc. 2001, 123, 5643.
3. Kelly, T.; Fogal, S.; Giblin, P.; Haynes, N.; Jeanfavre,
D.; Kishimoto, K.; Lai, G.; Lemieux, R.; Minolfi, E.;
Panzenbeck, M.; Reilly, P.; Tweedie, D.; Woska, J.; Wu,
J.-P. Presented at the 11th National Conference of the
Inflammation Research Association, New York, USA,
October 2002, S17.
4. Wu, J.-P.; Kelly, T. A.; Lemieux, R.; Goldberg, D. R.;
Emeigh, J. E.; Sorcek, R. J. Patent WO-2001007440,
2001.
5. (a) Yee, N. K. Org. Lett. 2000, 2, 2781; (b) Frutos, R. P.;
Stehle, S.; Nummy, L.; Yee, N. Tetrahedron: Asymmetry
2001, 12, 101.
Scheme 4. Regents and conditions: (a) KN(TMS)2,
(EtO)2POCl, THF, −20°C (92%); (b) NaI, TMSCl, H2O,
CH2Cl2 (75%).
6. Appel, R.; Kleinstuck, R.; Ziehn, K. Chem. Ber. 1971,
104, 1335.
7. The use of alternative dehydration conditions such as
Burgess reagent, p-TsCl/Et3N or Ph3P·Br2/Et3N failed to
give any of the desired 8.
8. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 18, 4171.
9. We noticed that the cyclization of 8 proceeded more
efficiently in the presence of Ph3PO, and the mechanistic
implications of this observation are currently under inves-
tigation.
10. Treatment of 5 with PBr3, POBr3 and (COBr)2 failed to
give any vinyl bromide analogous to 3.
Scheme 5. Reagents and conditions: (a) c-PentMgCl, SO2,
NCS, R2NH, THF (89%); (b) ArB(OH)2, (dppf)PdCl2,
K3PO4, DME (80–85%).
11. For representative examples see: (a) Powers, J. C. J. Org.
Chem. 1966, 31, 2627; (b) Russell, K.; Van Nivelt, C. E.
J. Heterocycl. Chem. 1995, 32, 299; (c) Langley, B. W. J.
Am. Chem. Soc. 1956, 2136; (d) Brennan, M. R.; Erick-
son, K. L.; Szmalc, F. S.; Tansey, M. J.; Thornton, J. M.
Heterocycles 1986, 24, 2879; (e) Bendall, J. G.; Payne, A.
N.; Screen, T. E. O.; Holmes, A. B. Chem. Commun.
1996, 11, 1067.
12. Barton, D. H. R.; Bashiares, G.; Fourrey, J.-L. Tetra-
hedron 1988, 44, 147.
13. (a) Su, Z.; Paquette, L. A. J. Org. Chem. 1995, 60, 764;
(b) Hirst, G. C.; Johnson, T. O.; Overman, L. E. J. Am.
Chem. Soc. 1993, 115, 2992.
dazo[1,2-a]imidazol-2-one LFA-1 inhibitors such as 2
in large quantities was accomplished using the proce-
dure described by Wu and co-workers4,19 (Scheme 5).
In conclusion, we have developed a new, reliable, regio-
controlled and safe route to a new class of LFA-1
inhibitors such as 2. The novel aspect of this route is
the transformation of amino amide 7 into iodide 3 in
four steps. Development of a reliable synthesis of 3 is
important because 3 is a key advanced intermediate
used in the synthesis of second-generation 1H-imi-
dazo[1,2-a]imidazol-2-one LFA-1 inhibitors.
14. Garcia Martinez, A.; Martinez Alvarez, R.; Garcia
Fraile, A.; Subramanian, L. R.; Hanack, M. Synthesis
1986, 222.
Acknowledgements
15. Lee, K.; Wiemer, D. F. Tetrahedron Lett. 1993, 34, 2433.
16. (a) Buon, C.; Bouysoou, P.; Coudert, G. Tetrahedron
Lett. 1999, 40, 701; (b) Nicolau, K. C.; Sui, G.-Q.;
Namoto, K.; Bernal, F. Chem. Commun 1998, 1757.
17. The TMSCl/NaI/water system generates HI in situ under
mild conditions, and has been used for the synthesis of
vinyl iodides via hydroiodination of alkynes, see:
Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675 and
references cited therein for further details.
The authors wish to thank Dr. V. Farina, Dr. Chris
Senanayake and Dr. L. Nummy for insightful
suggestions.
References
18. Immediate quench of the reaction after completion was
required, otherwise continuous exposure of the product 3
to the reaction conditions resulted in various amounts of
protodeiodination product 4.
1. For a detailed discussion of adhesion receptors of the
immune system, see: Springer, T. A. Nature 1990, 346,
425 and references cited therein.
19. Wu, J.-P.; Emeigh, J. Presented at the 219th National
Meeting of the American Chemical Society, Washington,
DC, March 2000; ORGN-201.
2. (a) Kelly, T. A.; Jeanfavre, D. D.; McNeil, D. W.;
Woska, J. R., Jr.; Reilly, P. L.; Mainolfi, E. A.; Kishi-
moto, K. M.; Nabozny, G. H.; Zinter, R.; Bormann,